Metal-free introduction of primary sulfonamide into electron-rich aromatics

We report herein a direct and practical synthesis of arylsulfonamides from electron-rich aromatic compounds by using in situ generated N-sulfonylamine as the active electrophile. Substrates include derivatives of aniline, indole, pyrrole, furan, styrene and so on. The reaction proceeds under mild conditions and tolerates many sensitive functional groups such as alkyne, acetate, the trifluoromethoxy group or acetoxymethyl ester. Applications of this method for the construction of metal ion sensors and fluorogenic dye have been demonstrated, thus highlighting the potential of this method for probe development.


Introduction
7][8][9] For example, by incorporating sulfonamide into classical rhodamine dyes, our group reported a general strategy in 2020 for making cell-permeable and uorogenic probes (socalled 'MaP'-dyes, Scheme 1A). 10,11Based on this design, we further reported a semi-synthetic calcium sensor in 2022 by combining the known calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N 0 N 0 -tetraacetic acid] with rhodamine dyes through a sulfonamide linkage. 12owever, a conventional method for sulfonamide synthesis was performed under strong acidic/basic conditions using a chlorosulfonic acidammonia sequence (Scheme 1B), which forced us to take a nine-step synthetic route with multiple protection/deprotection steps for the synthesis of 1. Meanwhile we were also interested in developing a potassium sensor using the MaP dye strategy, but the synthetic efficiency for accessing sulfonamide 2 with the conventional method was too low (0-1% yield).3][24][25][26][27][28][29][30][31][32][33][34] An electrochemical process for direct sulfonamide synthesis was reported in 2021 by the Waldvogel group, but primary sulfonamides were not accessed. 35These limitations motivated us to develop a direct method for the introduction of primary sulfonamide group into aromatic compounds.
3][44] In fact, N-sulfonylamine (or azasulfene) was proposed in Burgess's early report as an elusive intermediate for the preparation of the Burgess reagent, and trapping it with nucleophiles such as amine or alkene to form sulfamide or a cycloadduct was successfully demonstrated. 45,46owever, N-sulfonylamine was only detected and characterized by matrix-isolation IR spectroscopy in 2016, largely due to its high instability. 47Although its applications in synthetic chemistry were still limited, we envisioned that N-sulfonylamine could be a better electrophile than the Burgess reagent for making sulfonamides, in a similar way to sulfur trioxide for accessing sulfonic acids (Scheme 1D).

Results and discussion
We therefore explored the possibility of using in situ generated N-sulfonylamine for direct sulfonamide synthesis.N,N-dimethylaniline 3a was selected as a model substrate and ClSO 2 -NHBoc as an N-sulfonylamine precursor (Table 1).To our pleasure, formation of Boc-protected sulfonamide 4a at the para/ortho position was observed when treating a solution of 3a and a base with ClSO 2 NHBoc at room temperature for the in situ formation of N-sulfonylamine.Among the tested organic bases, DABCO gave the highest conversion as well as para/ortho selectivity (Table 1, entries 1-4).An inorganic base like Na 2 CO 3 gave products in poor yield and selectivity (Table 1, entry 5).In comparison to diethyl ether, dichloromethane as a solvent can further improve the conversion, albeit with lower para/ortho selectivity (Table 1, entry 6).In contrast, only 7% of 3a was consumed in the absence of a base while the rest was found to be protonated, which was then restored aer a basic aqueous workup (Table 1, entry 7).Lewis acid additives such as AlCl 3 or TMSOTf were unable to catalyze this Friedel-Cras type reaction (Table 1, entry 8), which was not surprising since it has always been a challenge for aniline derivatives to participate in other electrophilic aromatic substitution reactions like alkylation [48][49][50][51][52][53] or acylation. 54Switching from N-sulfonylamine to the Burgess reagent led to a lower conversion of 3a, while the DABCO based inner salt showed no reactivity (see ESI, Scheme S1 †).
With the optimal conditions in hand, we then examined the scope of the reaction with either diethyl ether or dichloromethane as the solvent (Scheme 2).Para-substituted sulfonamide 4a was obtained in 86% yield and the synthesis can be easily scaled up, delivering 1.3 grams of the product without losing efficiency.Facile removal of the Boc group was achieved by treating 4a with 6 N HCl solution at room temperature for 2 hours, and the primary sulfonamide 6a was obtained quantitatively by ltration aer neutralization.Anilines with cyclic or acyclic alkyl substituents on the nitrogen atom underwent the reaction well to give products 4b-h in yields ranging between 84 and 99%.This reaction was extended successfully to diphenylmethylamine and triphenylamine, with products 4i-j isolated in 91-92% yield.No erosion of the reactivity was observed with just one methyl group at the ortho position, but the conversion rate dropped to 10% when ortho positions were both occupied (products 4k-l).Substituents at the meta position, especially electron-donating groups, were found to have a strong impact on para/ortho selectivity.On switching from a methyl group to acetate or to a methoxy group, though the yield was not affected, the ratio of the ortho-substituted product gradually increased even when Et 2 O was used as the solvent (products 4m-o).With electron-withdrawing substituents at the meta position, the para-substituted product was obtained as the major product.For example, in the case of the triuoromethoxy group, parasubstituted 4p was isolated in 78% yield.A series of functional groups including alkynyl, triuoromethyl and the strongly Scheme 1 Our previous work using sulfonamides for fine-tuning rhodamine properties and further applications in creating metal ion sensors (A).Traditional methods for sulfonamide synthesis (B).Synthesis of sulfonamides from pre-functionalized substrates (C).This work using N-sulfonylamine for direct access to sulfonamides from electron-rich aromatic compounds (D).Substrates with one or more halogen atoms can also be tolerated and products 4t-x were obtained in 69-82% yield.Apart from aniline derivatives, other electron-rich aromatic compounds like indole or pyrrole with various substituents on the N atom were also tested under standard conditions and excellent yields were obtained in these cases (products 5a-d).
Furan can participate in the reaction as well, with product 5e isolated in 60% yield.When a vinyl group was present in the substrate, the reaction took place rst at the vinyl position before the aryl substitution happened (product 5f).However, efforts to further extend the reaction scope to include less electron-rich substrates, such as anisole, chlorobenzene, or azobenzene, were not successful (see ESI, Scheme S3 †).With our interest in developing semi-synthetic uorescent sensors, we then applied this reaction for introducing sulfonamide group into metal-ion binding moieties (Scheme 3).A simple substrate containing acetoxymethyl ester (AM ester) 7 was tested rst, giving the desired product 8 in 85% yield.Combining this step with Boc deprotection in a one-pot fashion by adding TFA to the reaction crude was also successful, and primary sulfonamide 9 was isolated in 80% yield.We then moved forward to test this reaction on the commercially available calcium chelator BAPTA-AM ester 10.a] Reaction conditions: 3 (0.50 mmol), DABCO (0.75 mmol), ClSO 2 NHBoc (1.0 mmol), in CH 2 Cl 2 (5.0 mL) at room temperature for 16 hours.Black dots indicated other reactive sites where regioisomers were formed.b] Et 2 O (5.0 mL) was used as solvent.
led to the formation of sulfonamide 2 in 46% yield which was hard to access by other methods.
Furthermore, a uorogenic MaP dye 18 was synthesized via amide coupling of 17 with 6a, which could be seen as the parent structure of these metal ion sensors but was not included in our previous studies (Scheme 4). 11We then installed chloroalkane, a ligand to label the HaloTag protein covalently, to 17 and 18 for accessing lactone 19 and lactam 20 as their HaloTag conjugates.Live-cell, no-wash uorescence imaging conrmed the high uorogenicity of 20, as compared to 19 (see ESI, Scheme S4 †).
In the end, we compared the reactivities of several different N-sulfonylamine precursors (Scheme 5).Besides ClSO 2 NHBoc, other carbamate-based reagents like ClSO 2 NHCbz, ClSO 2 NHAlloc and ClSO 2 NHTroc can also be used, yielding 4a with different protecting groups which can be readily removed by hydrogenation, palladium chemistry, or Zn, respectively.ClSO 2 NHBz can also be used as an N-sulfonylamine precursor, but the desired 4a-Bz was obtained in only 8% yield, likely due to the competing rearrangement reaction of N-sulfonylbenzamide at room temperature. 62Although FSO 2 NHBoc shows improved stability, it failed to deliver any product under standard conditions.Additionally, reagents without free N-H, such as ClSO 2 N(Boc) 2 and the commercial reagent morpholine-4sulfonyl chloride, cannot be used for transferring the sulfonamide group to 3a.Sulfamoyl chloride (ClSO 2 NH 2 ) also failed to give any product, probably due to the high pK a of its N-H bond compared to that of ClSO 2 NHBoc.

Conclusions
In summary, we have developed a practical and general strategy for introducing primary sulfonamide group into aniline derivatives as well as other electron-rich aromatic compounds such as indole, pyrrole, furan and alkenes.Owing to the mild reaction conditions, a series of functional groups were tolerated, especially the labile AM ester.With this method, several sulfonamides containing a metal ion chelator (Ca 2+ , Zn 2+ , Mg 2+ , and K + ) were rapidly accessed, underlining the potential of the method to rapidly generate complex chemical probes in the late stage.Efforts for further constructing and characterizing semi-synthetic uorescent probes through the MaP dye strategy are currently underway in our lab.

Table 1
Optimization of the reaction conditions a electron-withdrawing nitro group were well tolerated, giving the corresponding products in 19-86% yield (products 4q-s).